The recently published 5-year data from the PACIFIC study [1] show a significant and sustained improvement in survival of a median of one and a half years for patients with unresectable lung cancer (stage III NSCLC) when they receive the immunomodulatory drug durvalumab, a so-called checkpoint inhibitor, after pretreatment with radiation chemotherapy. This procedure definitely sets a new standard in advanced non-small cell lung cancer and gives new hope to patients with this serious disease.
Many people die of lung cancer every year. In patients with advanced stage III non-small cell lung cancer (NSCLC) that is not treatable by surgery, there are still good options for at least significantly slowing the progression of the disease; cures are also still possible. In this context, the sole so-called definitive radiotherapy plays an important role, since the most modern techniques can be used to take into account the respiratory motility and, in the course of treatment, the tumor’s response to radiation or the decrease in tumor volume, and to adjust the therapy. This ensures that the tumor is always irradiated with the maximum dose, but that the surrounding healthy tissue is spared as much as possible. Radiation therapy is often combined with chemotherapy. Here, a double positive effect comes into play: On the one hand, the radiation therapy itself destroys the tumor tissue, and on the other hand, it increases the response of the cancer cells to chemotherapy or an immunotherapy.
A few years ago, the PACIFIC trial [2] caused a sensation, in which progression-free patient survival after combined radiation chemotherapy was significantly improved by subsequent immunotherapy with durvalumab, a so-called checkpoint inhibitor. The prospective, double-blind, randomized, placebo-controlled, global phase III trial had enrolled 713 patients with unresectable, locally advanced stage III NSCLC (without progression after definitive radiochemotherapy of at least 2 cycles). 1-42 days after radiochemotherapy, 476 patients received durvalumab i.v. and 237 placebo for 12 months (2 : 1 randomization). Compared with placebo treatment, durvalumab prolonged overall survival by 32% and progression-free survival by 48% with an acceptable safety profile. According to these results, durvalumab (following the PACIFIC regimen) has already been established as the standard of care for inoperable stage III NSCLC after radiochemotherapy.
Now, five 5 years after the last patient in the PACIFIC trial was randomized, an updated analysis of survival data has been published [1]: Both a sustained survival benefit and freedom from progression were confirmed: 42.9% of patients were still alive after five years with durvalumab (vs. 33.4% with placebo); approximately one-third also had no tumor progression (vs. 19% with placebo). Overall, durvalumab reduced the risk of death by 31% (HR 0.69); at 12, 24, and 36 months, survival rates with durvalumab were 83.1%, 66.3%, and 57.0%, respectively, versus 74.6%, 55.3%, and 43.5% with placebo. Median survival increased from 29.1 to 47.5 months with durvalumab. “That’s 18 months more, and these results set completely new benchmarks in this setting,” explained Prof. Daniel Zips, MD, a radiation oncologist at CCC Tübingen-Stuttgart. “Such treatment outcomes in such a common cancer, which is often difficult to treat, are a tremendous advance clinically. Not only is remission maintained much longer than before, but new prospects for cure are created.” The expert sees here a paradigm shift in the therapy of advanced lung cancer and suspects a class effect of the checkpoint inhibitors. Radiotherapy remains an important pillar. “Radiation is what makes tumor cells particularly sensitive to the antibody in the first place and is therefore an indispensable part of the new standard of care.”
PD-L1 testing of the tumor is required for treatment with durvalumab. PD-L1 (“pro-grammed death-ligand 1”) is a biomarker or protein on cell surfaces that inhibits durvalumab. The test can be performed on tumor tissue using a simple staining technique in virtually any histology laboratory. It was not yet mandatory in the study, nor was it performed in advance in 37% of the study participants. “This had actually diluted the positive study result, because post-hoc analysis of the data showed that the therapy was even more effective in PD-L1-positive patients but had little effect in PD-L1-negative ones.” The approval of durvalumab requires PD-L1 testing prior to therapy initiation. Radiochemotherapy plus durvalumab administration is now being investigated in earlier tumor stages [3].
Literature
[1] de Wit M, Spigel DR, Faivre-Finn C et al. 5-year survival data of durvalumab after chemoradiotherapy for unresectable stage III NSCLC – an update of the PACIFIC study. 2021
[2] Antonia SJ, Villegas A, Daniel D et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 2017; 377 (20): 1919-29.
[3] Melillo G, Chand V, Yovine A, Gupta A, Massacesi C. Curative-intent treatment with durvalumab in early-stage cancers. Adv Ther 2021; 38: 2759-78.
https://doi.org/10.1007/s12325-021-01675-0
Source: German Society for Radiation Oncology e. V.
